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Ibrutinib Inhibits BTK Signaling in Tumor-Infiltrated B Cells and Amplifies Antitumor Immunity by PD-1 Checkpoint Blockade for Metastatic Prostate Cancer
SIMPLE SUMMARY: Metastatic prostate cancer has a poor clinical prognosis and is incurable. In recent decades, immune checkpoint blockade has revolutionized anticancer therapies and represents a potential way to control metastatic prostate cancer. Unfortunately, due to low immunoreactivity, patients...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
MDPI
2023
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10136622/ https://www.ncbi.nlm.nih.gov/pubmed/37190284 http://dx.doi.org/10.3390/cancers15082356 |
Sumario: | SIMPLE SUMMARY: Metastatic prostate cancer has a poor clinical prognosis and is incurable. In recent decades, immune checkpoint blockade has revolutionized anticancer therapies and represents a potential way to control metastatic prostate cancer. Unfortunately, due to low immunoreactivity, patients failed to achieve clinical benefits from PD-1/PD-L1 blockade. The underpinning mechanisms involved in the drug resistance of immune checkpoint blockade focus the research for metastatic prostate cancer treatment. In this study, we provide a novel combinational regimen with a kinase inhibitor and PD-1/PD-L1 axis blockade to overcome the above-mentioned drug resistance. We believe that our research will be helpful for the development of novel strategies for metastatic or late-stage prostate cancer immunotherapy. ABSTRACT: Metastatic prostate cancer (PCa) remains incurable and causes considerably diminished overall survival. Despite significant progress in pharmacotherapy, the disease prognosis remains unchanged. Immune checkpoint inhibitors (ICIs) have demonstrated effectiveness in treating various advanced malignancies, but their efficacy in metastatic PCa is relatively limited. Previous studies have confirmed the immunosuppressive role of tumor-infiltrating B cells (TIL-Bs) in the PCa microenvironment, which accounts for their poor immunogenic potency. In this study, we demonstrated that an oral kinase agent, ibrutinib, strongly potentiated anti-PD-1 checkpoint blockade efficacy and successfully controlled tumor growth in a murine orthotopic PCa model constructed using a metastatic and hormone-independent cell line (RM-1). We identified close relationships between TIL-Bs, Bruton’s tyrosine kinase (BTK), and immunosuppressive molecules by bioinformatics and histological analysis. An in vitro study showed that a low dose of ibrutinib significantly inhibited B cell proliferation and activation as well as IL-10 production through the BTK pathway. Moreover, ibrutinib-treated B cells promoted CD8(+) T cell proliferation and inhibitory receptor (IR) expression. However, the same dose of ibrutinib was insufficient to induce apoptosis in cancer cells. An in vivo study showed that ibrutinib monotherapy failed to achieve tumor regression in murine models but decreased B cell infiltration and inhibited activation and IL-10 production. More importantly, CD8(+) T cell infiltration increased with high IR expression. Ibrutinib synergized with anti-PD-1 checkpoint blockade enormously improved antitumor immunity, thereby reducing tumor volume in the same scenario. These data set the scene for the clinical development of ibrutinib as an immunogenic trigger to potentiate anti-PD-1 checkpoint blockade for metastatic PCa immunotherapy. |
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